Skip to main content

Alleviation of osteoarthritis by Trichostatin A, a histone deacetylase inhibitor, in experimental osteoarthritis

Molecular Biology Reports volume 37, pages 3967–3972 (2010)Cite this article

Abstract

This study investigated the effects of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) on cartilage degradation in an experimental model of osteoarthritis (OA). Thirty-two male New Zealand rabbits underwent unilateral anterior cruciate ligament transection (ACLT) on left knee joints to induce OA and were randomly divided into two groups (n = 16), the TSA group was injected intra-articularly with 0.3 ml TSA [250 ng/ml in the dimethylsulphoxide (DMSO)], the OA group received DSMO since 4 weeks after operation once a week for 5 weeks. Rabbits were killed seven days after the last injection. Left knee cartilage was harvested for morphological, histological and genetic analysis. Another ten rabbits were used for normal control and received no injection. The TSA group showed less cartilage degradation as compared to the OA group assessed by morphological and histological evaluation. Gene expression of matrix metalloproteinase-1 (MMP-1), MMP-3, MMP-13, and interleukin-1 (IL-1) was increased significantly in the OA group compared to the normal group. The elevated expression was reduced by TSA. Our results suggest that TSA could be considered as a potential agent for treatment for OA.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. Thirunavukkarasu K, Pei Y, Wei T (2007) Characterization of the human ADAMTS-5 (aggrecanase-2) gene promoter. Mol Biol Rep 34:225–231

    CAS  Article  PubMed  Google Scholar 

  2. Mizui Y, Yamazaki K, Kuboi Y et al (2000) Characterization of 5′-flanking region of human aggrecanase-1 (ADAMTS4) gene. Mol Biol Rep 27:167–173

    CAS  Article  PubMed  Google Scholar 

  3. Huang K, Wu LD (2010) Suppression of aggrecanase: a novel protective mechanism of dehydroepiandrosterone in osteoarthritis? Mol Biol Rep 37:1241–1245

    CAS  Article  PubMed  Google Scholar 

  4. Caterina JJ, Shi J, Kozak CA, Engler JA, Birkedal-Hansen H (2000) Characterization, expression analysis and chromosomal mapping of mouse matrix metalloproteinase-19 (MMP-19). Mol Biol Rep 27:73–79

    CAS  Article  PubMed  Google Scholar 

  5. Burrage PS, Mix KS, Brinckerhoff CE (2006) Matrix metalloproteinases: role in arthritis. Front Biosci 11:529–543

    CAS  Article  PubMed  Google Scholar 

  6. Rengel Y, Ospelt C, Gay S (2007) Proteinases in the joint: clinical relevance of proteinases in joint destruction. Arthritis Res Ther 9:221

    Article  PubMed  Google Scholar 

  7. Martel-Pelletier J, Welsch DJ, Pelletier JP (2001) Metalloproteases and inhibitors in arthritic diseases. Best Pract Res Clin Rheumatol 15:805–829

    CAS  Article  PubMed  Google Scholar 

  8. Neuhold LA, Killar L, Zhao W et al (2001) Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest 107:35–44

    CAS  Article  PubMed  Google Scholar 

  9. Dahlberg L, Billinghurst RC, Manner P et al (2000) Selective enhancement of collagenase-mediated cleavage of resident type II collagen in cultured osteoarthritic cartilage and arrest with a synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1). Arthritis Rheum 43:673–682

    CAS  Article  PubMed  Google Scholar 

  10. Tetlow LC, Adlam DJ, Woolley DE (2001) Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum 44:585–594

    CAS  Article  PubMed  Google Scholar 

  11. Goldring MB (2000) The role of the chondrocyte in osteoarthritis. Arthritis Rheum 43:1916–1926

    CAS  Article  PubMed  Google Scholar 

  12. Kobayashi M, Squires GR, Mousa A et al (2005) Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage. Arthritis Rheum 52:128–135

    CAS  Article  PubMed  Google Scholar 

  13. Bao JP, Chen WP, Wu LD (2010) Lubricin: a novel potential biotherapeutic approaches for the treatment of osteoarthritis. Mol Biol Rep. doi:10.1007/s11033-010-9949-9

  14. Glauben R, Sonnenberg E, Zeitz M et al (2009) HDAC inhibitors in models of inflammation-relatedtumorigenesis. Cancer Lett 280:154–159

    CAS  Article  PubMed  Google Scholar 

  15. Glauben R, Batra A, Fedke I et al (2006) Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol 176:5015–5022

    CAS  PubMed  Google Scholar 

  16. Leoni F, Zaliani A, Bertolini G et al (2002) The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits anti-inflammatory properties via suppression of cytokines. Proc Natl Acad Sci USA 99:2995–3000

    CAS  Article  PubMed  Google Scholar 

  17. Chabane N, Zayed N, Afif H et al (2008) Histone deacetylase inhibitors suppress interleukin-1beta-induced nitric oxide and prostaglandin E2 production in human chondrocytes. Osteoarthr Cartil 16:1267–1274

    CAS  Article  PubMed  Google Scholar 

  18. Young DA, Lakey RL, Pennington CJ et al (2005) Histone deacetylase inhibitors modulate metalloproteinase gene expression in chondrocytes and block cartilage resorption. Arthritis Res Ther 7:R503–R512

    CAS  Article  PubMed  Google Scholar 

  19. Wang X, Song Y, Jacobi JL et al (2009) Inhibition of histone deacetylases antagonized FGF2 and IL-1beta effects on MMP expression in human articular chondrocytes. Growth Factors 27:40–49

    Article  PubMed  Google Scholar 

  20. Nishida K, Komiyama T, Miyazawa S et al (2004) Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum 50:3365–3376

    CAS  Article  PubMed  Google Scholar 

  21. Lin HS, Hu CY, Chan HY et al (2007) Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br J Pharmacol 150:862–872

    CAS  Article  PubMed  Google Scholar 

  22. Nasu Y, Nishida K, Miyazawa S et al (2008) Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. Osteoarthr Cartil 16:723–732

    CAS  Article  PubMed  Google Scholar 

  23. Wu LD, Yu HC, Xiong Y et al (2006) Effect of dehydroepiandrosterone on cartilage and synovium of knee joints with osteoarthritis in rabbits. Rheumatol Int 27:79–85

    CAS  Article  PubMed  Google Scholar 

  24. Shikhman AR, Amiel D, D’Lima D et al (2005) Chondroprotective activity of N-acetylglucosamine in rabbits with experimental osteoarthritis. Ann Rheum Dis 64:89–94

    CAS  Article  PubMed  Google Scholar 

  25. Mankin HJ, Dorfman H, Lippiello L et al (1971) Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J Bone Joint Surg Am 53:523–537

    CAS  PubMed  Google Scholar 

  26. Bau B, Gebhard PM, Haag J et al (2002) Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro. Arthritis Rheum 46(10):2648–2657

    CAS  Article  PubMed  Google Scholar 

  27. Ailenberg M, Silverman M (2003) Differential effects of trichostatin A on gelatinase A expression in 3T3 fibroblasts and HT-1080 fibrosarcoma cells: implications for use of TSA in cancer therapy. Biochem Biophys Res Commun 302:181–185

    CAS  Article  PubMed  Google Scholar 

  28. Daheshia M, Yao JQ (2008) The interleukin 1beta pathway in the pathogenesis of osteoarthritis. J Rheumatol 35:2306–2312

    CAS  Article  PubMed  Google Scholar 

  29. Fernandes JC, Martel-Pelletier J, Pelletier JP (2002) The role of cytokines in osteoarthritis pathophysiology. Biorheology 39:237–246

    CAS  PubMed  Google Scholar 

  30. Leoni F, Zaliani A, Bertolini G et al (2002) The an-titumor histone deacetylase inhibitor suberoylanilide hydroxamic acidexhibits anti-inflammatory properties via suppression of cytokines. Proc Natl Acad Sci USA 99:2995–3000

    CAS  Article  PubMed  Google Scholar 

  31. Leoni F, Fossati G, Lewis EC et al (2005) The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med 11:11–15

    Article  Google Scholar 

  32. Yan C, Boyd DD (2007) Regulation of matrix metalloproteinase gene expression. J Cell Physiol 211:19–26

    CAS  Article  PubMed  Google Scholar 

  33. Ahn KS, Aggarwal BB (2005) Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann N Y Acad Sci 1056:218–233

    CAS  Article  PubMed  Google Scholar 

  34. Imre G, Gekeler V, Leja A et al (2006) Histone deacetylase inhibitors suppress the inducibility of nuclear factor-kappa B by tumor necrosis factor-alpha receptor-1 down-regulation. Cancer Res 66:5409–5418

    CAS  Article  PubMed  Google Scholar 

  35. Yin L, Laevsky G, Giardina C (2001) Butyrate suppression of colonocyte NF-kappa B activation and cellular proteasome activity. J Biol Chem 276:44641–44646

    CAS  Article  PubMed  Google Scholar 

  36. Davie JR (1997) Nuclear matrix, dynamic histone acetylation and transcriptionally active chromatin. Mol Biol Rep 24:197–207

    CAS  Article  PubMed  Google Scholar 

  37. Marks P, Rifkind RA, Richon VM et al (2001) Histone deacetylases and cancer: causes and therapies, Nat. Rev Cancer 3:194–202

    Google Scholar 

  38. Johnstone RW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287–299

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from Health Bureau of Zhejiang Province (2006A055).

Author information

Affiliations

  1. Department of Orthopedics Surgery, the Second Hospital of Medical College, Zhejiang University, JieFang Road 88#, 310009, Hangzhou, People’s Republic of China

    Wei-Ping Chen, Jia-Peng Bao, Peng-Fei Hu, Jie Feng & Li-Dong Wu

Authors
  1. Wei-Ping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jia-Peng Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peng-Fei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jie Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li-Dong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li-Dong Wu.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chen, WP., Bao, JP., Hu, PF. et al. Alleviation of osteoarthritis by Trichostatin A, a histone deacetylase inhibitor, in experimental osteoarthritis. Mol Biol Rep 37, 3967–3972 (2010). https://doi.org/10.1007/s11033-010-0055-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-010-0055-9

Keywords

  • Trichostatin A
  • Osteoarthritis
  • Matrix metalloproteinase
  • Interleukin-1